chr7-24722673-G-T

Variant names:

• chr7-24722673-G-T
• rs2521758
• NM_001127453.2:c.405-3455C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001127453.2(GSDME):​c.405-3455C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.614 in 152,068 control chromosomes in the GnomAD database, including 30,591 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.61 (30591 hom., cov: 32)
• Consequence: GSDME NM_001127453.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.69
• Publications: 4 publications found

Genes affected

GSDME (HGNC:2810): (gasdermin E) Hearing impairment is a heterogeneous condition with over 40 loci described. The protein encoded by this gene is expressed in fetal cochlea, however, its function is not known. Nonsyndromic hearing impairment is associated with a mutation in this gene. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

GSDME Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• autosomal dominant nonsyndromic hearing loss 5

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.967 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSDME	NM_001127453.2	c.405-3455C>A		intron_variant	Intron 3 of 9	ENST00000645220.1	NP_001120925.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GSDME	ENST00000645220.1	c.405-3455C>A		intron_variant	Intron 3 of 9		NM_001127453.2	ENSP00000494186.1

Frequencies

GnomAD3 genomes AF: 0.613 AC: 93181 AN: 151950 Hom.: 30521 Cov.: 32

Gnomad AFR AF: 0.803

Gnomad AMI AF: 0.298

Gnomad AMR AF: 0.653

Gnomad ASJ AF: 0.457

Gnomad EAS AF: 0.990

Gnomad SAS AF: 0.746

Gnomad FIN AF: 0.514

Gnomad MID AF: 0.535

Gnomad NFE AF: 0.480

Gnomad OTH AF: 0.570

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.614 AC: 93310 AN: 152068 Hom.: 30591 Cov.: 32 AF XY: 0.622 AC XY: 46222 AN XY: 74326

African (AFR) AF: 0.803 AC: 33289 AN: 41458

American (AMR) AF: 0.653 AC: 9984 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.457 AC: 1585 AN: 3470

East Asian (EAS) AF: 0.990 AC: 5133 AN: 5186

South Asian (SAS) AF: 0.747 AC: 3599 AN: 4818

European-Finnish (FIN) AF: 0.514 AC: 5431 AN: 10574

Middle Eastern (MID) AF: 0.537 AC: 158 AN: 294

European-Non Finnish (NFE) AF: 0.480 AC: 32653 AN: 67968

Other (OTH) AF: 0.574 AC: 1207 AN: 2104

Alfa AF: 0.537 Hom.: 4764

Bravo AF: 0.628

Asia WGS AF: 0.860 AC: 2991 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.045
DANN	Benign	0.40
PhyloP100		-1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2521758; hg19: chr7-24762292;